Baclofen reverses the hypersensitivity of dorsal horn wide dynamic range neurons to mechanical stimulation after transient spinal cord ischemia; implications for a tonic GABAergic inhibitory control of myelinated fiber input

Hao, Jing‐Xia; Xu, Xiao‐Jun; Yu, Yingying; Seiger, Åke; Wiesenfeld‐Hallin, Zsuzsanna

doi:10.1152/jn.1992.68.2.392

Cited by 157 publications

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“…Studies using animal models of SCI provide evidence indicating that changes in the spinal GABAergic system occur and contribute to central pain following SCI. After spinal ischemic injury in the rat, the behavioral and neuronal hypersensitivities are associated with reduced GABA immunoreactivity in the spinal cord and can be attenuated by activation of GABA receptors [12,13]. Similar observation has been reported in studies of rats with spinal hemisection injury [6].…”

Section: Introductionsupporting

confidence: 79%

Transplantation of GABAergic Neurons from ESCs Attenuates Tactile Hypersensitivity Following Spinal Cord Injury

et al. 2010

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We investigated the therapeutic potential of mouse ESCderived gamma-amino butyric acid (GABA)ergic neurons ($74% of total neurons in vitro) to reduce neuropathic pain following spinal cord injury (SCI) in rats. Spinal cord hemisection at the T13 segment, which is used as a rat SCI pain model, induced tactile hypersensitivity of the hind paw, as evidenced by decreased paw withdrawal thresholds in response to von Frey filaments, and also induced hyperexcitability of wide dynamic range neurons in the lumbar spinal cord in response to natural cutaneous stimuli. At 2 weeks posthemisection, GABAergic neurons (500,000 cells) were transplanted into the subarachnoid space of the spinal lumbar enlargement via a modified lumbar puncture technique. The transplantation of GABAergic neurons led to long-term attenuation of hemisection-induced tactile hypersensitivity and neuronal hyperexcitability as compared with vehicle-treated controls. These attenuations were reversed by the application of bicuculline and CGP52432, GABA-A and GABA-B receptor antagonists, respectively, but not by application of the serotonergic receptor antagonist methylsergide, indicating a specific restoration of spinal GABAergic inhibition. Histological data from sections of the lumbar cord in grafts demonstrated that 43.5% of surviving engrafted cells were neurons and located densely in the lower-medial portion of the dorsal funiculi in the spinal white matter. Among the observed neurons, 26.2% were GABAergic. The results suggest that subarachnoid transplantation of ESC-derived GABAergic neurons appear to restore spinal GABAergic inhibitory tone and can be a promising strategy to treat SCI-induced pain.

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Section: Introductionsupporting

confidence: 79%

Transplantation of GABAergic Neurons from ESCs Attenuates Tactile Hypersensitivity Following Spinal Cord Injury

et al. 2010

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“…An acute period of hypersensitivity (1 ± 5 days) is associated with reduced GABA immunoreactivity 39 and is attenuated by activation of GABA B receptors. 52 In contrast to acute hypersensitivity after ischaemic SCI, the chronic phase of hypersensitivity, with onset at 7 ± 50 days, does not depend on GABAergic mechanisms 46 but does respond to intrathecal application of opioids 53 and the alpha 2 noradrenergic agonist clonidine. 54 Interactions between opiate and cholecystokinin (CCK) segmental modulatory systems may play a role in the development of pain, 55 but this model has not ruled out the eects of altered downstream modulation upon damaged spinal cord segments.…”

Section: Experimental Modelsmentioning

confidence: 99%

Pain following spinal cord injury

2001

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Chronic pain is an important problem following spinal cord injury (SCI) and is a major impediment to eective rehabilitation. The reported prevalence of chronic SCI pain is variable but averages 65% with around one third of these people rating their pain as severe. The mechanisms responsible for the presence of pain are poorly understood. However, evidence from clinical observations and the use of animal models of SCI pain suggests that a number of processes may be important. These include functional and structural plastic changes in the central nervous system following injury, with changes in receptor function and loss of normal inhibition resulting in an increased neuronal excitability. A number of speci®c types of SCI pain can be distinguished based on descriptors, location and response to treatment. Nociceptive pain can arise from musculoskeletal structures and viscera and neuropathic pain can arise from spinal cord and nerve damage. The role of psychological and environmental factors also needs to be considered. Accurate identi®cation of these pain types will help in selecting appropriate treatment approaches. Current treatments employ a variety of pharmacological, surgical, physical and psychological approaches. However, evidence for many of the treatments in use is still limited. It is hoped that future research will identify eective treatment strategies that accurately target speci®c mechanisms. Spinal Cord (2001) 39, 63 ± 73Keywords: spinal cord injuries; pain; neuropathic pain; paraplegia; tetraplegia Historical overviewChronic pain is a major problem in those who have sustained a spinal cord or cauda equina injury.1 These patients usually have devastating neurological de®cits. A signi®cant proportion also suers from chronic pain. Riddoch 2 addressed the problem of pain after SCI in his 1917 paper although Munro's classic paper on spinal cord injuries in 1943 did not even mention the issue of chronic pain.3 After WW II, Botterell et al. 4described chronic pain in 12/103 SCI patients and 11 of these 12 had cauda equina injuries. Kuhn 5 reported that 0.234% of the injuries in WW II involved the spinal cord and that 22.5% of 113 patients with SCI had chronic pain. Prevalence/incidenceSince then, there have been numerous reports regarding the incidence and prevalence of pain following SCI. In 1962, Kaplan 6 attempted to classify SCI pains and stated that 37% of 52 SCI patients had chronic pain 1 year after injury and this increased to 50% by 5 years after injury. Davis 7 reported an incidence of 27% in 471 SCI patients. Richards et al.8 claimed that 77% of 88 SCI patients had chronic pain and that psychosocial variables predicted about 1/2 of the variance. Woolsey 9 identi®ed less than a 20% incidence of chronic pain in a group of 100 SCI patients.A number of more recent studies have all contributed data on the incidence and prevalence of pain after SCI.10 ± 17 The methodology and the patient population being studied appear to greatly in¯uence the reported incidence of SCI pain but across studies it appears...

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“…Failure of tonic or phasic inhibition may lead to states of hyperexcitability in some forms of pain (Hao, Xu, Yu, Seiger & Wiesenfeld-Hallin, 1992;Woolf & Doubell, 1994). It is possible that downregulation of plateau properties is important in shaping the activity of plateau-generating neurones.…”

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confidence: 99%

Inhibitory control of plateau properties in dorsal horn neurones in the turtle spinal cord in vitro

Russo

Nagy

Hounsgaard

1998

The Journal of Physiology

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1. The role of inhibition in control of plateau-generating neurones in the dorsal horn was studied in an in vitro preparation of the spinal cord of the turtle. Ionotropic and metabotropic inhibition was found to condition the expression of plateau potentials. 2. Blockade of ã_aminobutyric acid (GABAA) and glycine receptors by their selective antagonists bicuculline (10-50 ìÒ) and strychnine (5-20 ìÒ) enhanced the excitatory response to stimulation of the dorsal root and facilitated the expression of plateau potentials. 3. Bicuculline and strychnine also facilitated the generation of plateau potentials in response to depolarizing current pulses, suggesting the presence of tonic ionotropic inhibitory mechanisms in turtle spinal cord slices. 4. Activation of GABAB receptors also inhibited plateau-generating neurones. The selective agonist baclofen (5-50 ìÒ) inhibited wind-up of the response to repeated depolarizations induced synaptically or by intracellular current pulses. 5. Baclofen reduced afferent synaptic input. This effect was not affected by bicuculline or strychnine and was blocked by the selective GABAB receptor antagonist 2-hydroxysaclofen (2-OH_saclofen, 100-400 ìÒ). 6. Postsynaptically, baclofen inhibited plateau properties. Activation of GABAB receptors produced a hyperpolarization (7·0 ± 0·5 mV, mean ± s.e.m., n = 29) with an associated decrease in input resistance (22·7 ± 3·1 %, n = 24). These effects were blocked by extracellular Ba¥ (1-2 mÒ). 7. When the baclofen-induced hyperpolarization and shunt were compensated for by adjusting the bias current and the strength of the stimulus, baclofen still inhibited generation of plateau potentials. Wind-up and after-discharges were also inhibited by baclofen. These effects remained in the presence of tetrodotoxin (1 ìÒ) and were antagonized by 2_OH_saclofen. 8. The inhibition of plateau properties was observed even when the baclofen-induced hyperpolarization and shunt were blocked by Ba¥ and when potassium channels were blocked by Ba¥ (3 mÒ), tetraethylammonium (TEA, 15 mÒ) and apamin (0·25-0·5 ìÒ). The baclofensensitive component of the plateau potential was reduced by nifedipine (10 ìÒ), suggesting a modulation of postsynaptic L-type Ca¥ channels. 9. We suggest that inhibitory regulation of plateau properties plays a role in somatosensory processing in the dorsal horn. The inhibitory control of wind-up and after-discharges may be particularly significant in physiological and therapeutic control of central sensitization to pain.

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Baclofen reverses the hypersensitivity of dorsal horn wide dynamic range neurons to mechanical stimulation after transient spinal cord ischemia; implications for a tonic GABAergic inhibitory control of myelinated fiber input

Cited by 157 publications

References 0 publications

Transplantation of GABAergic Neurons from ESCs Attenuates Tactile Hypersensitivity Following Spinal Cord Injury

Transplantation of GABAergic Neurons from ESCs Attenuates Tactile Hypersensitivity Following Spinal Cord Injury

Pain following spinal cord injury

Inhibitory control of plateau properties in dorsal horn neurones in the turtle spinal cord in vitro

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